In our Forum discussion “journal club” series, the editors of Schizophrenia Bulletin provide access to the full text of a recent article. A short introduction by a journal editor gets us started, and then it's up to our readers to share their ideas and insights, questions, and reactions to the selected paper. So read on….

An introduction by Gunvant Thaker gets us started, and then it's up to our readers to share their ideas and insights, questions and reactions to these papers.

The majority of individuals with severe mental illnesses, such as schizophrenia and bipolar disorder, experience impairments in everyday functioning in real-world settings. These impairments occur early in the course of the illness and persist even after successful treatment of overt symptoms. Functional impairments are some of the main reasons for the high individual and societal burden associated with severe mental illnesses. In a recent paper published online in Schizophrenia Bulletin, Phil Harvey and colleagues argue that genetics may contribute to these impairments, although there are complex other determinants of real-world functional impairments, including environmental factors that need to be parsed out. One way of achieving this is to focus on measures of functional capacity that have robust psychometric properties and arguably are less influenced by environmental factors. The paper identifies a need for further examination of functional capacity measures as endophenotypes establishing their familial characteristics and heritability estimates.

Considering the burden associated with functional impairments, ideas presented by the paper are interesting and provide new directions. At the same time, it raises many questions for discussion: Do measures of functional disability represent much more complex phenotypes than clinical diagnosis, making them ill-suited for genetic studies? Successful gene hunting for complex phenotypes is likely dependent on identifying simple endophenotypes that are more proximal to genetic effects. Considering this, is the focus on measures of functional capacity misguided? Or, is such a focus likely to identify processes underlying the functional capacity measures and thus better suited for genetic studies as Harvey and colleagues propose?

I just wanted to make it clear that we think that the ability measures are the candidates, not the much more complex real-world outcomes. Our argument hinges on the fact that some of these skills-based measures are actually less complex than the neuropsychological tests that we know are potentially heritable. We know that those real world outcomes are affected by things outside of genetic control.

In a large, family-based study of schizophrenia spectrum disorder (PAARTNERS; Aliyu et al., 2006), we looked at functioning as indicted by common clinical indicators such as employment, living situation, education levels, and global functioning ratings. The primary aim of PAARTNERS was to examine neurocognitive performance as an intermediate phenotype for use in GWAS and other genetic studies of schizophrenia. That analysis showed significant heritability for components of neurocognition in schizophrenia spectrum disorder, supporting what others have reported. In a secondary analysis, we have looked at functioning; we also found it to be quite heritable and plan to report our findings soon. Also, unlike other studies that looked at both neurocognition and functioning, our data suggested that neurocognition was not a significant predictor of functioning within families, suggesting that it may to some extent be an independent trait. However, our study looked at “real world” complex aspects of functioning, which are multi-determined and difficult to analyze, although quite relevant clinically. Therefore, we also suggest taking a more focused, performance-based approach to functioning to attempt to determine its ongoing suitably as a quantitative trait in complex psychiatric disorders, including schizophrenia spectrum and bipolar disorders.

This is a provocative paper that makes a significant step towards deconstructing schizophrenia into elements that are more directly connected to the psychosocial disability experienced by patients and families. The disconnection between neurocognition and function is not unexpected. It is similar to the disconnection between neurocognition and symptoms and between symptoms and pathophysiological features, such as sensory gating dysfunction. Each level of dysfunction reflects multifactorial genetic and non-genetic inputs, with the most complex levels of dysfunction possibly reflecting elements that cause dysfunction across a much broader range of psychopathology than schizophrenia alone. However, caution should be exercised here. Multigenic traits may be quite heritable, but they do not necessarily reflect major gene effects from a single gene. Thus, they may not be good phenotypes for gene discovery.

While the genetic components of functional performance have yet to be fully investigated, their heritability invites genetic exploration. At this point, our knowledge of quantitative trait phenotypes related to schizophrenia, including functional performance-based measures, neurocognitive measures, or psychophysiologic task performance, is too limited to know for certain which are truly simpler and closer to the genes than others, so that broader investigation using all of these types of phenotypes is warranted. Indeed, as Phil Harvey notes above, some of the performance skills-based measures may be less complex than many of the neuropsychologic measures currently utilized in genetic studies. Several genetic investigations underway from Johns Hopkins, a large-scale VA cooperative study, and Long Island Jewish Medical Center should help clarify these questions.